The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
By xerogel is meant a dried gel. Silica xerogels are partly hydrolyzed oxides of silicium. Hydrolyzed oxide gels can be produced by a sol-gel process, which has been used for producing ceramic and glass materials for several years.
The sol-gel process is based on hydrolyzation of a metal-alkoxide and subsequent polymerization of the metal hydroxides as follows:Si(OR)4+H2O ---->HO—Si(OR)3+ROH  1)HO—Si(OR)3+3 H2O+ROH ------>Si(OH)4+4 ROH  2)Si(OH)4+Si(OH)4 ------->(HO)3Si—O—Si(OH)3+H2O  3)As the polymerization reaction progresses, additional chains, rings and three-dimensional networks are formed, and a gel, comprising water, the alcohol of the alkoxy group and the gel itself, is formed. The sol may also contain other additives, such as acids or bases, which are used as catalysts for the reaction. Further additives such as polyethylene glycol (PEG) can also be added to influence on the porosity of the gel. If alcohol and water are now extracted from the gel by washing and evaporation, a xerogel is obtained.
The polymerization of the remaining OH groups continues during the drying. The polymerization continues for a long time even after the gelation. This is called ageing. The further the polymerization proceeds, the more stable the gel or xerogel becomes. At room temperature, however, the polymerization will in fact stop after an ageing of a few weeks, and the xerogel will not become completely inert. If the temperature is raised, the polymerization reaction can be accelerated, the gel becomes more stable and shrinkage occurs, and internal stresses appear in the xerogel to an increasing degree.
The controlled release of therapeutic agents from biodegradable matrix has become increasingly important for implantable delivery systems, due to its advantages of safety, efficacy and patient convenience. The sol-gel technique offers new possibilities for incorporating biologically active agents within silica xerogels at room temperature process, and for controlling their release rates from silica xerogel matrix in time dependent manner (Nicoll et al. 1997; Ahola et al. 1998; Böttcher et al. 1998; Kortesuo et al., 1998; Sieminska et al., 1996). This sol-gel technology is cheap, versatile and simple, and silica xerogels produced by this technique are biocompatible and non-toxic materials (Kortesuo et al. 1998; Radin et al. 1998; Kortesuo et al. 1999). Earlier studies have shown that chemical and physical changes into the silica xerogel matrix have effect on the releasing behavior of biologically active agents because of the drug release from silica xerogel is the combined process of diffusion and matrix erosion.
A major concern with the use of artificial organs and biomedical devices is the untoward interactions of blood upon contacting a foreign surface. The most obvious complications are those related to the haemostatic mechanism, which can lead to thrombus formation and impaired function or occlusion of medical devices. Intravascular stenting is often used after angioplasty to prevent a reocclusion of the damaged vessel following dilation. One problem inherent to stent implantation is a possible restenosis. The process of restenosis is attributed to myointimal hyperplasia as well as to thrombus formation (Palmaz, 1993, Van Beusekom et al., 1993). The interaction of platelets with the stent surface may have significance not only due to their involvement in thrombus formation, but also by the release of platelet derived growth factor that may be included in the stimulation of smooth muscle cell growth (Palmaz, 1993, Ross, 1986). Heparin is routinely used for the prophylaxis of both surgical and medical thrombosis.
However, there is no disclosure or suggestion in prior art indicating that compositions for the controlled release of heparin could be achieved by incorporating heparin in a sol-gel derived silica xerogel, and that such a composition would be useful for treating and/or preventing thrombosis. Known heparin preparations are administered as injections. Thus, there is a great need for more convenient administration routes of heparin, especially for long acting, controlled release dosage forms of heparin.